ABSTRACT It is commonly accepted that implant wear particles, generated from the implant device, induce peri-prosthetic osteolysis, a form of chronic inflammatory bone resorption mediated by osteoclasts. Growing evidence suggests that older populations are more susceptible to bone osteolysis. There is a critical need for new strategies to prevent or treat peri-prosthetic osteolysis in the aging society of the U.S. However, the underlying mechanisms for aging-associated osteoclast precursor migration, especially to the peripheral bone lesions, remain elusive. Our earlier studies demonstrate that macrophage migration inhibitory factor (MIF) is chemotactic for blood circulating osteoclast precursors via its cognate receptor CXCR4 in vitro as well as in vivo in a mouse model of particle-induced calvaria osteolysis (Movila et al., 2016. JBMR).Also, the high mobility group protein B1 (HMGB1), recently identified as a central mediator of cellular senescence, significantly enhances MIF secretion from aging rather than young macrophages in vitro. Based on these lines of evidence, we hypothesize that the HMGB1/MIF axis plays a key role in the homing of circulating CXCR4+ OCPs to wear particle-induced osteolytic lesions in the aging population. In this application, Specific Aim 1 is designed to establish the role of HMGB1 in increased MIF production by peri-prosthetic macrophages of aging mice with particle-induced calvaria osteolysis. We will compare the role of HMGB1 and its receptors (TLR family of innate immune receptors and receptor for advanced glycation endproducts [RAGE]) relative to the release of MIF from peri-prosthetic macrophages of young (two month-old) and aged (twenty four month-old) wild type animals, both in vitro and in vivo. In Specific Aim 2, we will elucidate the molecular mechanisms by which MIF promotes chemotactic migration of circulating OCPs to particle-induced osteolysis lesions in senescent animals. We will establish the molecular mechanism underlying MIF-mediated age-dependent recruitment of OCPs to osteolysis lesions in young vs. aged mice by comparison of the known MIF receptors including, CD74, CXCR2 and CXCR4. For this purpose, real time locomotion of eGFP+CD11b+ OCPs in Csf1r-eGFP-knock-in mice will be monitored using FDA-approved state-of-the-art Cellvizio (Mauna Kea Technologies) intravital endoscopic imaging technology. The proposed research project represents one of the first investigations into the contribution of circulating OCPs to particle-induced bone lytic lesions in senescent organisms. Further, this study will provide a paradigm-shifting framework for the development of novel therapies against wear debris-induced osteolysis lesions in older people, targeting MIF activity.